chr4-39556568-G-A

Variant names:

• chr4-39556568-G-A
• rs780051052
• NM_174921.3:c.127C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_174921.3(SMIM14):​c.127C>T​(p.Pro43Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000245 in 1,589,120 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P43P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: SMIM14 NM_174921.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.74
• Publications: 0 publications found

Genes affected

SMIM14 (HGNC:27321): (small integral membrane protein 14) Predicted to act upstream of or within blastocyst hatching. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

UGDH-AS1 (HGNC:40601): (UGDH antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174921.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMIM14	NM_174921.3	MANE Select	c.127C>T	p.Pro43Ser	missense splice_region	Exon 4 of 5	NP_777581.1	Q96QK8
	SMIM14	NM_001317896.2		c.127C>T	p.Pro43Ser	missense splice_region	Exon 5 of 6	NP_001304825.1	Q96QK8
	SMIM14	NM_001317897.2		c.127C>T	p.Pro43Ser	missense splice_region	Exon 4 of 5	NP_001304826.1	Q96QK8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMIM14	ENST00000295958.10	TSL:1 MANE Select	c.127C>T	p.Pro43Ser	missense splice_region	Exon 4 of 5	ENSP00000295958.4	Q96QK8
	SMIM14	ENST00000865444.1		c.127C>T	p.Pro43Ser	missense splice_region	Exon 4 of 5	ENSP00000535503.1
	SMIM14	ENST00000865445.1		c.127C>T	p.Pro43Ser	missense splice_region	Exon 5 of 6	ENSP00000535504.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000262 AC: 6 AN: 228614 AF XY: 0.0000404

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000557

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000251 AC: 36 AN: 1437070 Hom.: 0 Cov.: 30 AF XY: 0.0000210 AC XY: 15 AN XY: 714540

African (AFR) AF: 0.00 AC: 0 AN: 32276

American (AMR) AF: 0.00 AC: 0 AN: 36892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.00 AC: 0 AN: 80842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.0000299 AC: 33 AN: 1104904

Other (OTH) AF: 0.0000506 AC: 3 AN: 59340

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74262

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.12	T
PhyloP100		6.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.51
Sift	Benign	0.053	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.46
MutPred		0.29		Gain of glycosylation at P43 (P = 0.0317)
MVP		0.34
MPC		1.4
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.42
gMVP		0.66
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs780051052; hg19: chr4-39558188;